Fluorine‐ and Trifluoromethyl‐Substituted Biphenyl Derivatives: Promising Antimicrobial Agents Targeting Escherichia coli FabH

ABSTRACT

This study investigates the synthesis, antibacterial activity, structure–activity relationships (SARs), and molecular docking of F‐ and CF₃‐substituted biphenyl derivatives (5A–5K) as potential antimicrobial agents. Ten novel biphenyl derivatives were synthesized, incorporating trifluoromethyl (CF₃) and fluorine (F) substitutions, to evaluate their efficacy against various bacterial strains, including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumoniae. Antimicrobial assays demonstrated that the F substitution significantly enhanced antibacterial activity, with the bis‐F derivative (5D) showing improved potency compared to the other compounds. Molecular docking studies revealed strong binding affinities between the compounds and the target enzyme, Escherichia coli FabH, suggesting a promising mechanism of action. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions indicated favorable drug‐like properties for most compounds, with low toxicity and good oral bioavailability. The SAR analysis further confirmed that bis‐F substitution at the meta‐position of the biphenyl backbone (5D) contributed synergistically to the compounds' antimicrobial efficacy. These findings highlight the potential of these derivatives as novel antibacterial agents.